Steroid gem difluorides of the androstane and pregnane series



United States Patent Ofiflce 3,189,524 Patented June 15, 1965 r 3,189,624 STEROID GEM DIFLUORIDES OF THE ANDRO- STANE AND PREGNANE SERIES John Fried, Plainfield, Glen E. Arth, Cranford, and William H. Jones, Meluchen, N.J., assignors to Merck & Co., Inc., Rahway, N.J., a corporation of New Jersey No Drawing. Filed July 28, 1960, Ser. No. 45,793 6 Claims. (Cl. 260397.5)

wherein R can be either hydrogen or halogen, and R can be an acyl group or hydrogen, (ii) 3,3-difluoro-4- androstene-17B-ol and esters thereof having the general formula:

. where R can be either hydrogen or halogen, and R can be an acyl group or hydrogen, (iii) 20,20-difluoro-5- pregnene-3fl-ol and esters thereof having the following general formula:

Where R'is an acyl group or hydrogen. 7 p

The steroid-gem difiuorides of this invention such as 3,3-difluoro-androstane-175-01 acetate, 3,3'-difiuoro-4-androstene-17Bol acetate, 20,20-difluoro-5-pregnene-3,8-ol acetate and 2-chloro-3,3-difluoro-androstane 1718-01 acetate are anti-androgenic agents. More over, these compounds at higher levels exhibit no androgenic activity.

Generally, gem difluorides may be prepared from ketones by the reaction of sulfur tetrafluoride with the particular ketone. The reaction of sulfur tetrafluoride with certain ketones has been found to require specific conditions for maximum yield of gem difluoride.

It is therefore an object of this invention to provide steroid-gem difiuorides.

Another object of this invention is to provide a process whereby halogenated gem difluorides maybe prepared.

A further object of this invention is to prepare pure steroid-gem difluorides.

Other objects of this invention will appear as the description proceeds.

It has been found that the compounds of the invention may be prepared by reacting sulfur tetrafluoride with a ketone steroid. The reaction, in order to proceed, requires the following conditions:

(l) A pressure greater than approximately 500 lbs. per square inch.

(2) An excess of sulfur tetrafluoride.

(3) Sulfur tetrafluoride solvent.

Preferably the molar ratio of sulfur tetrafluoride to keto steroid should be greater than approximately 50:1. It has also been found that technical grade sulfur tetrafluoride having the following composition:

1 SF, 90-94%. (2) Thionyl fluoride 59%. (3) Chlorine V (4) Sulfur monochloride Approx. 1%. (5) Sulfur dichloride when used in a reaction to make steroid-gem difluorides, wherein an excess of this steroid-gem difluoride is required, essentially all of the steroid is chlorinated in a position adjacent to the ketone gorup of the keto steroid. This can be explained by an example where excess sulfur tetrafiuoride is required. Twelve grams of sulfur tetrafluoride are "used to form 3,3-difluoro androstane-17B-ol acetate from 500 mgs. of androstane-17B-ol-3-one acetate, wherein a large portion of the sulfur tetrafluoride is used as a solvent. The sulfur tetrafluoride being commercialgrade can contain as much as 1% by weight of chlorine. In other words, 12 grams of sulfur tetrafluoride contains 0.12 gram of chlorine which is equal to 0.0016 mole of chlorine. Now, 500 mgs. of androstane-17B-ol-3-one acetate represents 0.0015 mole of that steroid, consequently, the probability is very high that 0.0015 mole of chlorinated steroid will be formed before any sulfur tetrafluoride will react with the steroid. Hence, the reaction mass will contain 2 chloro-3,3-difiuoro androstaue-17f3-ol acetate when commercial sulfur tetrafluoride is reacted with androstane-17B-ol-3-one acetate.

Consequently, in order to make steroid-gem d-ifluorides.

wherein no chlorination will take place, the chlorination agents in the commercial sulfur tetrafiuon'de must be removed prior to the reaction of sulfur tetrafluoride with the keto steroids. The removal of chlorinating agents is facilitated by the intimate contact of the commercialgrade of sulfur tetrafluoride with mercury.

In carrying out the process of the present invention heretofore described in the example, the following procedure is outlined: A keto steroid is placed in a bomb. To this bomb commercial-grade sulfur tertafluoride is added whereby the ratio of sulfur tetrafluoride to ketosteroid is greater than approximately 50:1. The bomb is closed and heated to a temperature of approximately C. for two hours. During this time interval, the

' ing structure:

"1han1 a mo pheric." 100 g;

7 pressure" in the bombreaches a range of approximately 1000 2000 lbs. per square inch. The compound formed by this process is the gem-difluoro alpha-chloro steroid. I

In order to make the pure 'gem-difluorosteroid, the following general procedure is used: The keto-steroid to be fluorinated is placed in a bomb; To this bomb sulfur tetrafiuoride which has been previously separated from T 'chlorinating agents is added. The molarratio of sulfur The tetrafiuoride to keto-steroid. is greater than 50: 1. bomb'is closed and heated at atemper ature of 50 C.

fora period of greaterthan two hours. During this time interval, the pressure in the bomb (is 'in the range of 1000-2000 lbs. per square inch. The compound formed by using this procedure is the steroid gem-difiuoride.

The following examples illustrate methods of carrying out the present invention, but it is to be'understood that these examples are given for purposes of illustration and not of limitation. V V

1 V i V Example p v a 500mg. of androstane-l7fi-ol 3-one acetate having the 7 structure:

' is placedin' a stainless steel bomb having a volume of 20 cc; To this bomb, 12 g. of sulfur tetrafiuoride (technical) V. and 0.05 ml; of boron trifluoride diethyl ether V 3)- 2 )z' l During this time interval,

2000 psig A compound is formed having the follow- (201110103,3-difluoroandrostane-l7B-olacetate) M.P. 180-182 C. Fd.: C, 64.35, H, 7.99 'CI, 9.51; F, 8.71.

7 Example 2 An experiment is carried out similar to that'of Example 1 using androstene-17fl-ol-3-one' acetate, except that the is added. The bombis closed and heated at a tempera- V a ture of 80 C. for two hours. the pressure in the bomb should be in the range of 1000a added to the bombthrough an open valve. After this mercury is introduced into the bomb, the valve is closed. The bomb is then removed from the .Dry Ice-acetone slurry and exposed to room temperature for about one I hour. The bomb is then agitated by shaking for-16 hours in a Rocking Shaker. (manfactured by the'Am'ericanlnstrument Company) operating at 36 rpm. The

valve on the bomb is then connected tothe valve'on a The second steel bomb, 7 having a volume of 500 cc. is evacuated and placedina 7 Dry Ice-acetone slurry.

second' bomb by a steel tube.

The valves on the bombs are the 'original, bomb'distilled into'the. second bomb, leav ing the liquid mercuryin the first bomb. This distilled SP contains no chlorinating agents. 3'1

The product formed has the following structure? (3,3-(Hfinoroandrostane-17B-ol acetate) 7 M.P. 135-l37 C. F11: C, 70.90; H,.9.19; F, 9.52.

Example 3 V 250 mg. of 4 -androstene-l7;3-ol-3-one' acetate is placed in astainless steel bomb having. a volume of'20 cc; To

this bomb, two drops of a 10% solution of boron trifluoride'etherate is added. The bomb is then closed'andf.

cooled to -80 C. 19.5 of sulfur tetrafluoride purified by the process described in Example '2 isdistilled into i the bomb and the valve on the bomb is closed; The mixture is heated inside the. bomb at '80 C. for v tvvohougrs at a pressure of approximately 1 500 p.s.i.g; After this] period of time, the contents of the bombare removed and extracted with chloroform. The chloroform extract is washed with an excess amount of aqueous 1 sodium bicarbonate. The extract is then dried and evaporated.

The solid which is obtained is then extracted withipetroa leum ether. This petroleum ether extract is dried, and a sulfur tetrafluoride used' is purified by the following x process:

tetrafluoride (technical) is thereby reduced to 80". C.

V SR (technical) has the followingcomposition:

(4) Sulfur monochloride (5) Sulfur dichloride The pressure within the bomb is then very much lower 1 of liquid mercury then Approx. 1

-A bomb of carbon steel construction containing one:

'pound of sulfur tetrafluoride (technical) having a volume of 500 tie, at a temperature of 26 C. and a pressure 7 of 150 p.s.i.g., is immersed in aDry Ice-acetone slurry for .a period of one hour. The temperature of the sulfur The contents of the bomb ar e extracted with chloroform. The chloroform extract is dried, and the residue is then f compound having the following structure is obtain'edz, v

Example .4

a 1 g. of 5 pregnene-Sfi-ol ZO-one acetate is placed in a '20 cc; stainless steel bomb; The bomb is cooled to C. To the bomb 19 g. of sulfurtetrafluoride purified by the processof Example 2 is added. Also addedrt-o the 1 bomb is 0.10 mlaof a- 10% solution in'ethe r ofjboron. 'trifluoride 'etheratef The valve 'on the bomb is, closed and 1 the bomb is heated for two hours at 80? C.' .a ndiat a. pressure of l000 p.s.i.g.i The bomb is then a'llowed to cool to room'temperatu're (approximately 25f iC.) and.

remain at 25 C.'for 20 hours. The bombis then vented.

opened and the SP in 5 6 extracted with petroleum ether. A compound having the acetate being in the range of 50 to 1 up to approximately following structure is obtained: 200 to 1.

2. 20,20-difluoro-5-pregnene 313-01 compounds having F the following formula: 5 CH3 I F F I3 I\ 10 AcOQ (20, 2O-diflnoro 5-pregnene 3B-ol-acetate) 15 R0 Various changes and modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the annexed 2 chioroaa3'dlfluomandmstane'17/301 acetateclaims, they are to be considered as part of our invention. 0 3,3'dlfluom'androstane'175' acetate- What is claimed 5. 3,3-d1fluoro-4-androstene-175-01 acetate.

1. The process for the production of 3,3-diifuoro-andro- 20120'dlfluorospregnene'3isol acetatestane-17fl-0l acetate comprising the steps of reacting androstane-17B-ol-3-one acetate with sulfur tetrafluoride, said sulfur tetrafiuoride being free of chlorinating agents, 25 in the presence of boron trifluoride etherate, the molar LEWIS GOTTS Primary Exammer' ratio of sulfur tetrafluoride to androstane-17B-ol-3-one L. H. GASTON, IRVING MARCUS, Examiners.

wherein R is selected from the group consisting of lower hydrocarbon acyl and hydrogen.

No references cited. 

2. 20,20-DIFLUORO-5-PREGNENE 3B-OL COMPOUNDS HAVING THE FOLLOWING FORMULA: 